The retinoic acid-related orphan receptor (ROR) isoforms RORα, RORβ, and RORγ are members of the steroid nuclear hormone receptor superfamily, and play prominent roles in a variety of biological processes including organ development, immunity, lipid homeostatsis and metabolism, and circadian rhythms (Jetten et al. NURSA 2009, 7, 1). The ROR family members are composed of both a ligand-binding domain (LBD) and a DNA-binding domain (DBD). Ligand binding causes a conformational change that modulates binding of co-regulatory proteins: agonists recruit co-activators; antagonists and inverse agonists disrupt the binding of co-activators or enhancing the binding of co-repressors thereby repressing the transcription of target genes (Fauber et al. J. Med. Chem. 2014, 57, 5871).
Retinoic acid-related orphan receptor γ thymus (RORγ, also referred to as RORc and NR1F3) is encoded by Rorc; human and mouse RORγ share high sequence homology, and nearly identical binding site homology (Jin, L. et al. Mol. Endocrinol. 2010, 24, 923). Mammalian RORγ exists in two distinct isoforms, RORγ and RORγt, which possess indentical LBDs and differ only in their N-terminal sequences (Medvedev et al. Gene 1996, 181, 199). Expression of the RORγt isoform is restricted to lymphoid organs including the thymus, whereas RORγ is more broadly expressed (liver, muscle, kidney), similar to RORαwhich is also found in brain and adipose tissue (Kurebayashi, S. et al. Proc. Natl. Acad. Sci., U.S.A. 2000, 97, 10132). RORβ is localized to the cerebral cortex (Hirose, T. et al. Biochem. Biophys Res. Commun. 1993, 194, 1371). RORγt is critical for the development of lymph nodes and Peyer's patches and for the normal differentiation of T helper-17 (Th17) cells, γδ T cells, and LTi cells (Sun et al. Science 2000, 288, 2369).
RORγt is an obligatory transcription factor that controls the differentiation of naive CD4+ T cells into Th17 lineage, and regulates transcription of the effector cytokine IL-17 in Th17 cells and cells of the innate immune response in both rodents and humans (Ivanov, I. et al. Cell 2006, 126, 1121). Pro-inflammatory cytokines including IL-17A, IL-17F, and IL-22 produced by Th17 cells and other RORγt+ lymphocytes activate and direct the immune response to extracellular pathogens (Ebert, G. et al. Nat. Immunol. 2004, 5, 64). Disruption of RORγ by genetic ablation of Rorc in mice attenuates disease severity in murine models of autoimmunity and inflammation including experimental autoimmune encephalomyelitis (EAE) induced by antigenic peptide, imiquimod-induced psoriasiform dermatitis, and allergic airway disease. Dysregulation of IL-17 transcription and secretion has been implicated multiple human autoimmune disorders including psoriasis, rheumatoid arthritis, inflammatory bowel disease (IBD), asthma, and multiple sclerosis (MS) (for example, see: Yang, X. et al. Immunity 2008, 28, 29; Pantelyushin, S. et al. J. Clin. Invest. 2012, 122, 2252; Leppkes, M. et al. Gastroenterology 2009, 136, 257; and Tilley, J. et al. J. Immunol. 2007, 178, 3208). The outcome of recent clinical trials with neutralizing antibodies to IL-17A and its receptor IL-17RA serve to highlight the role of this cytokine in psoriasis disease pathogenesis (Papp, K. et al. New. Engl. J. Med. 2012, 366, 1181; Leonardi, C. et al. New. Engl. J. Med. 2012, 366, 1190. The attenuation of IL-17 production from activated T cells and Th17, for example via inhibition or RORγt, may offer a similar therapeutic benefit.
Therapeutic agents exist to treat a variety of inflammatory and autoimmune diseases, but there still remains a significant unmet medical need in these therapeutic areas. Given the role of IL-17 in human disease and the validation of IL-17 and RORγ as targets in murine disease models, compounds capable of modulating RORγt activity are contemplated to provide a therapeutic benefit in the treatment of multiple immune and inflammatory disorders.